Complement Deficiencies

Article Last Updated: Jun 2, 2006
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Synonyms and related keywords: C1qrs deficiency, C3 deficiency, C2-C4 deficiency, C5-9 deficiency, terminal membrane attack complex deficiency, MAC deficiency, mannan-binding lectin deficiency, MBL deficiency, immune system, bacterial infection, sepsis, host defense mechanism, immune complex disease, systemic lupus erythematosus, SLE, complement activation, disseminated meningococcal disease, Streptococcus pneumoniae, S pneumoniae, Haemophilus influenzae, H influenzae, Neisseria meningitidis, N meningitidis, meningococcemia

INTRODUCTION


Background

The complement system is part of the innate immune system. The complement system plays an important part in defense against pyogenic organisms. It promotes the inflammatory response, eliminates pathogens, and enhances the immune response. Deficiencies in the complement cascade can lead to overwhelming infection and sepsis.

In addition to playing an important role in host defense against infection, the complement system is a mediator in both the pathogenesis and prevention of immune complex diseases, such as systemic lupus erythematosus (SLE). These findings underscore the duality of the complement system. It has a protective effect when functioning in moderation against pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not kept in check.

Knowledge about the complement system is continuing to expand. New studies point to the complex interplay between the complement cascade and adaptive immune response, and complement is also being studied in association with ischemic injury as a target of therapy. Although the complement system is part of the body's innate, relatively nonspecific defense against pathogens, its role is hardly primitive or easily understood. This article outlines some of the disease states associated with complement deficiencies and their clinical implications.

Pathophysiology

The complement cascade consists of 3 separate pathways that converge in a final common pathway. The pathways include the classical pathway (C1qrs, C2, C4), the alternative pathway (C3, factor B, properdin), and the lectin pathway (mannan-binding lectin [MBL]). The classical pathway is triggered by interaction of the Fc portion of an antibody (immunoglobulin [Ig] M, IgG1, IgG2, IgG3) or C-reactive protein with C1q. The alternative pathway is activated in an antibody-independent manner. Lectins activate the lectin pathway in a manner similar to the antibody interaction with complement in the classical pathway. These 3 pathways converge at the component C3. Although each branch is triggered differently, the common goal is to deposit clusters of C3b on a target. This deposition provides for the assembly of the membrane attack complex (MAC), components C5b-9. The MAC exerts powerful killing activity by creating perforations in cellular membranes.

Deficiencies in complement predispose patients to infection via 2 mechanisms: (1) ineffective opsonization and (2) defects in lytic activity (defects in MAC). Specific complement deficiencies are also associated with an increased risk of developing autoimmune disease, such as SLE.

An intricate system regulates complement activity. The important components of this system are various cell membrane–associated proteins such as complement receptor 1 (CR1), complement receptor 2 (CR2), and decay accelerating factor (DAF).

In addition to these cell surface–associated proteins, other plasma proteins regulate specific steps of the classic or alternative pathway; for example, the proteins factor H and factor I inhibit the formation of the enzyme C3 convertase of the alternative pathway. Similarly, the enzyme C1q esterase acts as an inhibitor of the classic pathway serine proteases C1r and C1s. Deficiency of any of these regulatory proteins results in a state of overactivation of the complement system, with damaging inflammatory effects. Two clinical manifestations of such deficiencies are paroxysmal nocturnal hemoglobinuria and hereditary angioedema, both of which are discussed in other eMedicine articles (see Paroxysmal Nocturnal Hemoglobinuria and Angioedema).

Frequency

International

Complement deficiencies are relatively rare worldwide, and estimates of prevalence are based on results from screening high-risk populations. Retrospective studies of persons with frequent meningococcal infections report varying prevalence based on geographic location. In populations with recurrent meningococcal infection, the prevalence rate is as high as 30%. Individuals with C1q deficiency have a 93% chance of developing SLE. Similarly, C1rs deficiency has a 57% association with SLE and C4 deficiency has a 75% association with SLE.

Mortality/Morbidity

Race

Sex

Age


CLINICAL


History

Infants may have Leiner disease, which manifests as recurrent diarrhea, wasting, and generalized seborrheic dermatitis. The defect in persons with Leiner disease is usually attributed to a defect of the fifth component of complement (C5). However, a child was described by Sonea and associates who had Leiner disease associated with diminished C3, and another was described by Goodyear and Harper with a low level of the fourth component of complement and reduced neutrophil mobility Thus, the C5 defect may not be the sole cause of Leiner disease, as has been suggested; diminished C3 or C4, or C5 dysfunction or deficiency with hypogammaglobulinemia or other lymphoid deficiency, is also required for its expression.
 
The 3 major sequelae of complement deficiencies, based on the pathophysiology of each defect, are (1) defects that result in inadequate opsonization, (2) defects in cell lysis, and (3) the association of complement deficiencies with immune complex diseases.

Physical

Causes


DIFFERENTIALS


Hypocomplementemia
Hypogammaglobulinemia
Immunoglobulin A Deficiency
Immunoglobulin D Deficiency
Immunoglobulin G Deficiency
Immunoglobulin M Deficiency
Immunosuppression
Meningococcal Infections
Meningococcemia
Sepsis, Bacterial
Septic Shock
Systemic Lupus Erythematosus
Urticaria

Other Problems to be Considered

Childhood erythroderma
Childhood seborrheic dermatitis
Hypocomplementemic urticarial vasculitis syndrome


WORKUP


Lab Studies

Imaging Studies

Other Tests

Procedures


TREATMENT


Medical Care

Consultations

Diet

Activity


MEDICATION


Cephalosporins are often used for treatment of N meningitidis infection in patients with complement deficiency. Third- or fourth-generation cephalosporins are used for coverage of infection with any of the encapsulated bacteria.

Drug Category: Antibiotics

Therapy must cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity results whenever feasible.

Drug NameCeftriaxone (Rocephin)
DescriptionThird-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Adult DoseMeningitis: 2 g IV qd for 14-21 d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsProbenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAdjust dose in renal impairment; caution in breastfeeding and allergy to penicillin

Drug NameCefepime (Maxipime)
DescriptionFourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage.
Adult Dose1-2 g IV q12h for 5-10 d; may administer higher or more frequent doses depending on severity of infection
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsProbenecid may increase effects; aminoglycosides increase nephrotoxic potential
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAdjust dose in severe renal insufficiency (high doses may cause CNS toxicity); prolonged use may predispose to superinfection


FOLLOW-UP


Further Inpatient Care

Further Outpatient Care

In/Out Patient Meds

Deterrence/Prevention

Complications

Prognosis

Patient Education


MISCELLANEOUS


Medical/Legal Pitfalls